Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity

Heather Bowling, Guoan Zhang, Aditi Bhattacharya, Luis M. Pérez-Cuesta, Katrin Deinhardt, Charles A. Hoeffer, Thomas A. Neubert, Wen Biao Gan, Eric Klann, Moses V. Chao

Research output: Contribution to journalArticle

Abstract

Although antipsychotic drugs can reduce psychotic behavior within a few hours, full efficacy is not achieved for several weeks, implying that there may be rapid, short-term changes in neuronal function, which are consolidated into long-lasting changes. We showed that the antipsychotic drug haloperidol, a dopamine receptor type 2 (D2R) antagonist, stimulated the kinase Akt to activate the mRNA translation pathway mediated by the mammalian target of rapamycin complex 1 (mTORC1). In primary striatal D2R-positive neurons, haloperidol-mediated activation of mTORC1 resulted in increased phosphorylation of ribosomal protein S6 (S6) and eukaryotic translation initiation factor 4E-binding protein (4E-BP). Proteomic mass spectrometry revealed marked changes in the pattern of protein synthesis after acute exposure of cultured striatal neurons to haloperidol, including increased abundance of cytoskeletal proteins and proteins associated with translation machinery. These proteomic changes coincided with increased morphological complexity of neurons that was diminished by inhibition of downstream effectors of mTORC1, suggesting that mTORC1-dependent translation enhances neuronal complexity in response to haloperidol. In vivo, we observed rapid morphological changes with a concomitant increase in the abundance of cytoskeletal proteins in cortical neurons of haloperidol-injected mice. These results suggest a mechanism for both the acute and long-term actions of antipsychotics.

Original languageEnglish (US)
Article numberra4
JournalScience Signaling
Volume7
Issue number308
DOIs
StatePublished - Jan 14 2014

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Haloperidol
Antipsychotic Agents
Neurons
Corpus Striatum
Cytoskeletal Proteins
Proteomics
Ribosomal Protein S6
Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors
S 6
Phosphorylation
Dopamine Receptors
Protein Biosynthesis
Machinery
Mass spectrometry
Mass Spectrometry
Carrier Proteins
Proteins
Phosphotransferases
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Bowling, H., Zhang, G., Bhattacharya, A., Pérez-Cuesta, L. M., Deinhardt, K., Hoeffer, C. A., ... Chao, M. V. (2014). Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity. Science Signaling, 7(308), [ra4]. https://doi.org/10.1126/scisignal.2004331

Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity. / Bowling, Heather; Zhang, Guoan; Bhattacharya, Aditi; Pérez-Cuesta, Luis M.; Deinhardt, Katrin; Hoeffer, Charles A.; Neubert, Thomas A.; Gan, Wen Biao; Klann, Eric; Chao, Moses V.

In: Science Signaling, Vol. 7, No. 308, ra4, 14.01.2014.

Research output: Contribution to journalArticle

Bowling, H, Zhang, G, Bhattacharya, A, Pérez-Cuesta, LM, Deinhardt, K, Hoeffer, CA, Neubert, TA, Gan, WB, Klann, E & Chao, MV 2014, 'Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity', Science Signaling, vol. 7, no. 308, ra4. https://doi.org/10.1126/scisignal.2004331
Bowling H, Zhang G, Bhattacharya A, Pérez-Cuesta LM, Deinhardt K, Hoeffer CA et al. Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity. Science Signaling. 2014 Jan 14;7(308). ra4. https://doi.org/10.1126/scisignal.2004331
Bowling, Heather ; Zhang, Guoan ; Bhattacharya, Aditi ; Pérez-Cuesta, Luis M. ; Deinhardt, Katrin ; Hoeffer, Charles A. ; Neubert, Thomas A. ; Gan, Wen Biao ; Klann, Eric ; Chao, Moses V. / Antipsychotics activate mTORC1-dependent translation to enhance neuronal morphological complexity. In: Science Signaling. 2014 ; Vol. 7, No. 308.
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